It has been demonstrated that kinetic resolution of racemates crystallizing in the form of conglomerates can be accomplished by carrying out the crystallization in the presence of small amounts of resolved additives, the stereochemical molecular structure of which resembles that of one of the enantiomers of the said racemic mixture. According to that process the non-polymeric inhibitors were added in rather large quantities (up to 10% wt/wt of racemic mixture). In addition such additives were occluded in the bulk of the precipitating crystals, in typical amounts of 0.5-1.5%. Furthermore, the additive cannot be separated from the precipitating crystals, see U.S. Pat. No. 4,533,506, granted Aug. 6, 1985; see also Addadi et al., J. Am. Chem. Soc., 104 4610 (1982).
In the present invention the use of polymeric inhibitors makes it possible to reduce the quantity of the additive by up to a factor of 10 or more.
The invention relates also to a process of resolution as set out above, where the racemate is provided in adjacent compartments of the resolution cell, separated by a suitable membrane, there being added to the first compartment an inhibitor of D-form crystallization, and to the other compartment an inhibitor of L-form crystallization. The result is that in one compartment essentially pure L-form enantiomer is obtained, and in the other D-form. This is made possible by the fact that contrary to the simple additives used before, the polymeric forms do not pass through such membranes.
The invention also relates to this process of separation where a two-compartment device with a membrane is used and to such separation device for this purpose. Various polymers can be used. As example, the invention is illustrated with reference to certain poly-(N.sup..epsilon. -acryloyl-L- or -D-amino acid) and poly-(N.sup..epsilon. -methacryloyl-D- or -L-amino acid) as the compounds which are used as inhibitors, the amino acid bound to the polymer being chosen according to the racemate which is to be resolved.
We have found that addition in solution of poly-(N.sup..epsilon. -acryloyl-L-lysine) (L-PAL) or poly-(N.sup..epsilon. -methacryloyl-L-lysine) (L-PMAL) M.W. or poly-[L-.alpha.-glutamyl)N-Acryloyl)hydrazide])L-PGAH) with different molecular weights in 0.1-1% wt/wt to a supersaturated solution of D,L-glutamic acid.HCl, (Glu.HCl) brings about a preferred crystallization of D-glutamic acid.HCl (D-Glue.HCl). Similarly, addition of poly-(N.sup..epsilon. -acryloyl-D-lysine) (D-PAL) or the methacryloyl analogue or D-PGAH allows the L-glutamic acid to precipitate. Furthermore, we have found that from a supersaturated aqueous solution of D,L-asparagine (Asn) addition of (L-PAL) or (L-PMAL) allows the preferred precipitation of D-asparagine monohydrate, (D-Asn.H.sub.2 O) and the addition of D-analogue polymers allows the separation of L-asparagine monohydrate (L-Asn.H.sub.2 O). Similarly, the addition of (L-PAL) or (L-PMAL) in 0.1-1% wt/wt to a supersaturated solution of D,L threonine (DL-Thr), brings about preferred crystallization of D-Threonine (D-Thr). Addition of (D-PMAL) or (D-PAL) leads to preferred crystallization of L-threonine (L-Thr).
Analogously, poly-(N-acryloyl-(p-aminobenzoyl)-D-secphenethylamide) (D-PA-PAB-PHA) allows the preferential crystallization of L-sec-phenethylalcohol as its 3,5-dinitrobenzoate from a racemic mixture. Inclusion of poly-(N-acryloyl-(p-aminobenzoyl)-L-secphenethylamide) (L-PA-AB-PHA) causes the preferred precipitation of the D-form. Analogously, the addition of the poly(P-acrylamido-L-phenyl alanine) (L-PA-PhE) or poly-(acryloxy-L-p-tyrosine) (L-PAO-Tyr) or the corresponding methacryloyl polymers allow the preferential crystallization of D-histidine.HCl.H.sub.2 O (D-HIS.HCl.H.sub.2 O) from a racemic mixture both at T&gt;45.degree. C. and T&lt;45.degree. C., where the conglomerate phase is metastable. Further, the addition of poly-(p-acrylamido-D-phenyl alanine) (D-PA-Phe) or poly-(acryloxy-D-p-tyrosine) (D-PAO-Tyr) or the corresponding methacryloyl polymer allows the preferential crystallization of L-histadine.HClH.sub.2 O from the racemic mixture. Similarly, the addition of (L-PAL) or (L-PA-Phe) or (L-PMAL) or (L-PAO-Tyr) or the corresponding methacryloyl polymers allows the preferential crystallization of D-p-hydroxphenyl-glycine-p-toluenesulphonate (D-pHPGpTS). The addition of any of the same D polymers results in the preferential crystallization of L-pHPGpTS. In a similar way, the addition of poly-(p-acrylamido-L-.alpha.-methyl-phenyl alanine) or the corresponding methacryloyl polymer allows the preferential crystallization of D-.alpha.-methyl-DOPA (3,4-dihyroxy-.alpha.-methyl-phenyl alanine). The addition of any of the same D polymers allows preferential crystallization of L-.alpha.-methyl-DOPA.
A similar resolution can be effected by using a device comprising two compartments separated by a membrane, provided with means for agitation. The L-type polymer is in one compartment (A) while the D-type polymer is in the second compartment (B). The polymer cannot diffuse through the membrane while the molecules of the substrate equilibrate (diffuse through the membrane).
Our previous patent, U.S. Pat. No. 4,533,506 describes that racemic conglomerates can be resolved by small molecular weight additives. We have now found that soluble polymers are much more efficient and useful. The fact that the additive is chemically bound to a polymer backbone, taking advantage of the cooperative effect, makes it possible to introduce the polymer in the desired solution in a very reduced amount (up to 1% wt/wt) of the racemic mixture to be resolved. In addition the polymer is not occluded in the crystals but remains in solution. Improved resolution, i.e. high chemical and optical yield of the desired enantiomer is achieved. Since the additive is linked to a polymer of high molecular weight, it allows carrying out the resolution of a racemic mixture in a device of two compartments separated by a membrane.